1. Field of the Invention
The present invention is concerned with an improved extracorporeal hemodialysis blood treatment method, wherein use is made of a technique for effective regional, extracorporeal anticoagulation of the patient's blood. More particularly, it is concerned with such an improved method which involves infusion of a citrate anticoagulant into the blood at a relatively low level, followed by treatment of the blood, subsequent infusion of a calcium compound into the blood in order to restore the coagulative properties thereof, and final return of the blood to the patient.
2. Description of the Prior Art
In the past few decades extracorporeal blood treatments such as hemodialysis and charcoal resin hemoperfusion have become relatively commonplace. In such techniques, blood is withdrawn from the patient, treated as desired, and returned to the patient. For example, in hemodialysis, the withdrawn blood is passed through a dialyzing unit along with an acetate or bicarbonate-based dialysate. In the dialyzer, toxins in the blood pass through semi-permeable membranes separating the blood and dialysate, in order to reduce the toxin concentration in the patient's blood. Hemoperfusion on the other hand basically involves passing the patient's blood through a specially designed charcoal resin filter prior to return of the blood to the patient.
In extracorporeal blood treatments of the type outlined above, anticoagulation of the blood is generally considered a necessary prerequisite to avoid clotting. That is to say, if the patient's blood is withdrawn in its normal condition, in passage through treatment apparatus the blood clots which form effectively impair treatment. The conventional technique for anticoagulation of blood has involved the use of heparin injection of the patient. The problems with heparin-based anticoagulation are generally twofold, namely, systemic anticoagulation of the patient and destruction of blood elements (platelets and leukocytes) resulting from deleterious interactions of blood cells with the dialyzing membrane or charcoal resins.
Systemic anticoagulation of patients is oftentimes quite undesirable because of hemorrhagic tendencies so frequently encountered in uremic or otherwise acutely ill patients. Moreover, hemorrhagic complications are serious and limiting problems encountered in actively bleeding renal failure (acute or chronic) patients, in post operative patients (especially cardiovascular procedures), in the ill septic patient and in acute hepatic failure. In the past, there have been attempts to limit the systemic effects of heparin by "regional" use of protamine to neutralize heparin in blood being returned to the patient and infusing small continuous doses of heparin (limited systemic heparinization) as opposed to loading doses. The expedients have however failed to circumvent hemorrhagic complications. Indeed, in a recent study addressing this problem, these two methods (heparin+protamine vs. limited systemic heparinization) hemorrhagic complications were noted in 10 to 19 percent of a group of patients with renal failure (Kidney Internat., 16:513-18, 1979).
Another problem occurring with conventional hemodialysis and in particular with resin hemoperfusion is the development of thrombocytopenia and leukopenia. A complement mediated blood cell membrane-resin/dialyzer membrane interaction leads to cell damage and in vivo sequestration of injured cells. Life threatening thrombocytopenia resulting from charcoal perfusion in hepatic failure necessitates platelet transfusions. Granulocytopenia and thrombocytopenia resulting from hemodialysis and charcoal resin hemoperfusion are of special concern in the septic patient, the acute bleeding uremic patient, and in post operative patients with renal failure.
It is also known that citrate anion is an extremely effective anticoagulative substance, which operates by complexing with calcium ion in the blood. In fact, a study has heretofore been undertaken to investigate with possibility of using citrate anticoagulants in the context of hemodialysis ("Regional Anticoagulation During Hemodialysis Using Citrate", Morita et al., The American Journal of the Medical Sciences, July, 1961, pp. 72-82. In the Morita et al. study, citrate anticoagulant was added to blood withdrawn from a patient, followed by dialysis of the blood and return thereof to the patient. However, the techniques described in this article were fraught with a number of serious problems, and were never adopted.
Specifically, Morita et al. described the use of trisodium citrate.2H.sub.2 O as a regional anticoagulant to replace heparin during hemodialysis and showed significant increases in the coagulation time of the blood exiting the hemodialyzer. However, use of the trisodium citrate gave unacceptable elevations of arterial plasma sodium (hypernatremia); in addition, because the dialysis treatment removed calcium ion from the patient's blood, hypocalcemia resulted. In an attempt to resolve these problems, Morita et al. attempted to employ monosodium dihydrogen citrate, and to add calcium ion at the dialyzer. While the use of a monosodium dihydrogen citrate did reduce the hypernatremia problem, its low pH (3.8) and the amount of free citric acid added (about 1000 milliequivalents for 6 hour treatment), blood acidosis problems were encountered. Furthermore, addition of calcium ion at the dialyzer (through use of a calcium-containing dialysate) caused undue complexation with the added citrate, thereby requiring still further initial citrate infusion. Thus, the solutions attempted by Morita et al. led only to further unacceptable difficulties.
In short, while the Morita et al. work demonstrated that citrate anion could be used as an effective anticoagulant during extracorporeal hemodialysis, the techniques therein employed created serious and even life-threatening problems.
In another recent development of Babb et al., reported in Artificial Organs, Apr. 7, 1979, pp. 470ff. and entitled "Design Criteria For An Extracorporeal Chemotherapeutic System To Continuously Modify Sickle Cell Hemoglobin", a technique was described for a cyanate treatment of the blood of sickle cell patients. As an adjunct to this treatment, an anticoagulant system was described wherein trisodium citrate was infused into withdrawn blood at a level of 10.2 millimoles citrate anion per liter of blood, followed by cyanate treatment, dialysis to remove cyanate, infusion of CaCl.sub.2 and heparin, and return of the blood to the patient. However, this sickle cell treatment necessarily involves blood flows (up to 70 ml/min.) which are excessively slow for conventional hemodialysis or hemoperfusion; moreover, use of heparin is objectionable for the reasons outlined above.